The present invention concerns compositions having physiological activities, including but not limited to anti-tumor activity and hypoglycemic effects (i.e. blood sugar level reducing effects). More particularly, compositions are taught that comprise active ingredients found in extracts of the fruiting bodies and/or mycelia culture (including the culture solution in addition to the mycelia) of fungi that belong to polyporaceae Basidiomycotina, such as Ganoderma Lucidum and/or Coriolus versicolor, and extracts obtained from the root of a Araliaceae plant. Methods for making and using such compositions are also taught.
The fruiting bodies and mycelium culture (which means only the mycelium and the mixture of the mycelium and the culture solution of the mycelium, hereinafter simply referred to as xe2x80x9cthe culturexe2x80x9d) of Ganoderma Lucidum, which belongs to aphyllophoral polyporaceae Basidiomycotina, have been known as natural medicines since ancient times. In addition to its various beneficial effects, it has been known that the polysaccharides and other low molecular weight components contained in these medicines have a variety of anti-tumor activities. Also, substances having various physiological activities, including anti-tumor activities, also have been extracted from the fruiting bodies of Coriolus versicolor, which belongs to polyporaceae Basidiomycotina.
Moreover, the roots of plants that belong to Araliaceae, including ginseng (Daucus carota), and their extracted components, also have independently been used as natural medicines since ancient times, and have been known to have numerous beneficial effects.
Generally speaking, although various therapeutic methods that incorporate treatment and prophylaxis by means of natural medicines are advantageous, because the natural medicines usually do not have adverse unwanted effects, the efficacy of known natural medicines is often minimal. While it has been empirically and experimentally known that both the extracted components of Basidiomycotina and the extracted components of ginseng have useful beneficial effects, combination of these specific components and the consequent synergistic amplification of their physiological activities caused by combining these components have not been known.
The inventors have discovered that compositions comprising extracted components derived from Basidiomycotina and extracted components derived from the roots of plants that belong to Araliaceae have remarkably potent anti-tumor activity. In addition, the inventors have discovered that such compositions can reduce blood sugar levels in hyperglycemic individuals (hereinafter xe2x80x9chypoglycemic effectsxe2x80x9d). Although not wishing to be bound by theory, the inventors believe that the physiological activities of these compositions may be related to their oxidation-reduction potential.
Thus, in one aspect of the present teachings, compositions are taught that include active ingredients that are found in one or more types of Basidiomycotina that belong to polyporaceae Basidiomycotina and active ingredients that are found in the root of a plant that belongs to Araliaceae. The active ingredients may be synthetically made or may be extracted, for example, from Ganoderma Lucidum and/or Coriolus versicolor and medicinal ginseng, which may be, e.g., Panax ginseng and/or Panax japonicus. The compositions preferably exhibit an oxidation-reduction potential of less than about +1230 mV, when dissolved in an aqueous solution, and more preferably less than about +900 mV. Such compositions may comprise a therapeutically effective amount of the active ingredients of these components. Such compositions may be administered, for example, to patients having tumors and/or to patients having high blood glucose levels.
Although the present teachings specifically contemplate active ingredients extracted from natural products, of course, synthetically made active ingredients that exhibit the herein-described effects are also contemplated.
In another aspect of the present teachings, compositions are taught that include extracted components of one or more types of Basidiomycotina that belong to polyporaceae Basidiomycotina and extracted components of the root of a plant that belongs to Araliaceae. Preferably, the oxidation-reduction potential of such compositions is about +1230 mV or less.
In another aspect of the present teachings, compositions are taught in which Ganoderma Lucidum and/or Coriolus versicolor is/are the above-mentioned one or more types of Basidiomycotina.
In another aspect of the present teachings, compositions are taught that comprises a therapeutically effective amount of the above-mentioned components. In one representative example, the compositions comprise components extracted from between about 0.5 and 2 parts per weight of the root of an Araliaceae plant and about 2 parts per weight of the above-mentioned Basidiomycotina. Preferably, the components are extracted from the fruiting bodies of Basidiomycotina. The Araliaceae plant preferably belongs to the family of medicinal ginseng and more preferably, the Araliaceae plant is Panax ginseng and/or Panax japonicus. 
In another aspect of the present teachings, compositions are taught that may be utilized as anti-tumor agents. In another aspect of the present teachings, compositions are taught that exhibit hypoglycemic effects. Methods of treatment utilizing such compositions are provided.
Various methods of manufacturing such compositions having such physiological activities are also taught. Representative examples are provided, such as obtaining components from a solution having an appropriate oxidation-reduction potential, which solution can be obtained by hot water extraction of one or more types of polyporaceae Basidiomycotina and the root of an Araliaceae plant. Preferably, the one or more types of Basidiomycotina may be Ganoderma Lucidum and/or Coriolus versicolor. Such components may be extracted in a ratio of about 0.5 and 2 parts per weight of Araliaceae root to about 2 parts per weight of the above-mentioned Basidiomycotina. The Araliaceae root preferably is medicinal ginseng and more preferably is Panax ginseng and/or Panax japonicus. Naturally, therapeutically effective compositions may be manufactured using different techniques that provide substantially the same effects.
Other objects, features and advantages of the present invention will be readily understood after reading the following detailed description together with the accompanying claims.
The active ingredients of the present compositions may be made in various ways, including but not limited to synthesis techniques or isolation techniques. In one preferred method of making the present compositions, the active ingredients are derived from the extracted components of one or more types of Basidiomycotina that belong to polyporaceae Basidiomycotina and the extracted components of the root of a plant that belongs to Araliaceae. Polyporaceae Basidiomycotina includes Ganoderma Lucidum, Coriolus versicolor and other related fungi. More preferably, the extracted components can be obtained from the fruiting bodies and/or mycelium culture (including the culture solution in addition to the mycelia) of one or more types of Polyporaceae.
Preferably, the Basidiomycotina is selected from one or more types of Ganoderma Lucidum and Coriolus versicolor. More preferably, a combination of Ganoderma Lucidum and Coriolus versicolor may be used. Taxonomical identification of the types of Basidiomycotina used herein is based on identifications provided in xe2x80x9cPrimary Color Picture Book of Japanese Mushroomsxe2x80x9d written by Imazeki and Hongou (Hoiku Co).
One representative example of Ganoderma Lucidum is Reishi fungus (Ganoderma Lucidum). Although this fungus breeds well on trees in nature, the native fungus is scarce. However, it can also be artificially cultivated. The fungus is glossy and consists of a waxy cap and a stalk having a length that may reach approximately 15 cm. The color of the fruiting body is red, blue, yellow, white, purple and black. The fungus has white strands and grows on tree stumps and/or around the base of a tree weakened by a disease.
Coriolus versicolor fungus naturally grows in the western part of Japan, especially in Shinshuu (particularly in Nagano Prefecture) and the Shikoku and Kyushu islands. In nature, this fungus is a xylophilic fungus that breeds especially well on broad-leafed trees. This Basidiomycotina breeds well in nature, can be artificially cultivated and also grown in a cell culture, with no restrictions. Preferably, the naturally grown fungus is used.
Preferably, the fruiting bodies of the fungi and/or a culture of the fungus body are used. The fruiting bodies can be prepared by air-drying at room temperature in the dark.
When Ganoderma Lucidum is used, it is particularly recommended to use naturally ripened black fruiting bodies. When Coriolus versicolor is used, it is recommended to use naturally grown fruiting bodies that were gathered in summer and air-dried at room temperature in the dark.
Preferably, the medicinal ginseng is an Araliaceae plant, which includes Panax quinquefolium L., Panax notogingseng, Panax japonicus C. A. Meyer, in addition to Panax ginseng C. A. Meyer. Preferably, Panax ginseng and/or Panax japonicus are used. More preferably, Panax japonicus is used. The roots of any of these types of ginseng may be used. Further, a single type of Araliaceae plant can be used or a combination of 2 or more types also can be used. Plants belonging to the Umbelliferae family also can be used as a substitute for the Araliaceae plant.
Suitable compositions can be obtained by extraction techniques using water. Although the extraction can be conducted using water at room temperature, preferably hot water is used. The raw materials for the Basidiomycotina extracted components and the Araliaceae extracted components can be separately extracted using hot water and then these extracts can be mixed, or a mixture of the Basidiomycotina and the root of the Araliaceae plant can be mixed together and extracted using hot water. For extraction using hot water, the raw materials may be crushed, sliced or powdered. Preferably, the raw materials are crushed into splinters. More preferably, splinters are approximately 5 mm in size.
The temperature of the hot water used for the hot water extraction preferably may be between about 80xc2x0 C. and about 100xc2x0 C. and more preferably, between about 90xc2x0 C. and about 95xc2x0 C. The recommended extraction time is at least 1 hour, preferably 2 hours or more and most preferably 2.5 hours or more. Preferably, the extraction time is limited to about 3 to 4 hours. The extraction process may be conducted using a reflux condenser.
While no special restrictions are placed on the quantity of water used in relation to the extraction raw materials, preferably a ratio of approximately 500 parts per weight of water to about 10 to 20 parts per weight of raw materials is used for the extraction. The concentration of an extraction solution obtained using such a weight ratio (especially if a reflux condenser is used) is typically a suitable concentration for direct administration without additional processing.
The extraction raw materials can be removed from the extraction solution obtained by filtration or other known methods. If needed, the extraction solution filtrate and supernatant can be condensed and used as a concentrated solution. In addition, by evaporating the water component, a solid (powder-like) extracted component can also be obtained and, if needed, the required dry extracted component can be obtained by drying or other known methods.
With respect to the administration form and the dosage form of the composition, additives for pharmaceutical manufacturing or for stabilization of the extracted component naturally can be added during the condensation or drying process.
The extraction raw materials can be used in a ratio of about 15 parts per weight of Basidiomycotina to about 1.5-6 parts per weight of the root of an Araliaceae plant. Preferably, about 2-4 parts per weight of the Araliaceae root is used for about 15 parts per weight of Basidiomycotina. More preferably, about 3 parts per weight of the Araliaceae root is used for about 15 parts per weight of Basidiomycotina.
In such a combination, Ganoderma Lucidum and/or Coriolus versicolor may be selected as the Basidiomycotina component. Preferably, Ganoderma Lucidum and Coriolus versicolor are used. A preferred ratio for the total quantity of Basidiomycotina is between about 1 and 4 parts per weight of Coriolus versicolor to about 2 parts per weight of Ganoderma Lucidum. Preferably, a ratio of about 1 part per weight of Coriolus versicolor to about 2 parts per weight of Ganoderma Lucidum is be used. More specifically, about 5 parts per weight of Coriolus versicolor, about 1.5-6 parts per weight of the root of an Araliaceae plant (preferably Panax japonicus) and about 10 parts per weight of Ganoderma Lucidum are used. More preferably, about 5 parts per weight of Coriolus versicolor, about 3 parts per weight of the root of an Araliaceae plant (preferably Panax japonicus) and about 10 parts per weight of Ganoderma Lucidum are used.
In addition, about 10 parts per weight of Coriolus versicolor, about 1.5-6 parts per weight of the root of an Araliaceae plant (preferably Panax japonicus) and about 5 parts per weight of Ganoderma Lucidum may be used.
Another preferred ratio is about 0.5-2 parts per weight of the root of an Araliaceae plant and about 2 parts per weight of Basidiomycotina. More preferably, a ratio of about 0.75-1.25 parts per weight of the root of an Araliaceae plant to about 2 parts per weight of Basidiomycotina is used. Most preferably, about 1 part per weight of the root of an Araliaceae plant to about 2 parts per weight of Basidiomycotina is used.
More specifically, Ganoderma Lucidum and Coriolus versicolor are used as Basidiomycotina in a ratio of 1 part per weight of Coriolus versicolor, about 0.5-2 parts per weight of the root of an Araliaceae plant and about 1 part per weight of Ganoderma Lucidum. More preferably, about 0.75-1.25 parts per weight of the root of an Araliaceae plant can be used, and most preferably 1 part per weight can be used.
In another embodiment, about 5-10 parts per weight of Coriolus versicolor, about 3-10 parts per weight of the root of an Araliaceae plant and about 10 parts per weight Ganoderma Lucidum are used. Preferably, the root of Panax japonicus is selected as the root of the Araliaceae plant.
For any of the above-mentioned combination, either Ganoderma Lucidum and Coriolus versicolor (i.e., the fruiting bodies of either) may be used alone as Basidiomycotina. Preferably, Panax ginseng or Panax japonicus is used as the Araliaceae plant component. More preferably, Panax japonicus can be used, but therapeutically effective compositions also can be obtained even if Panax ginseng is substituted for Panax japonicus. 
A representative method will now be described for making a composition having a 1:1:1 weight ratio of the fruiting bodies of Ganoderma Lucidum, the fruiting bodies of Coriolus versicolor and Panax japonicus (root). For example, 6 g of the fruiting bodies of Ganoderma Lucidum, 6 g of the fruiting bodies of Coriolus versicolor and 6 g of Panax japonicus can be combined, mixed and crushed into splinters of approximately 5 mm in size 500 ml of distilled water can be added to this crushed product and the mixture can be boiled for 3 hours using a reflux condenser. After which, the solution is filtered to yield a stock solution composition.
This stock solution may be diluted if necessary for certain uses. If dilution is necessary, various dilution ratios may be utilized, such as dilution ratios ranging between 2 and 300 fold, preferably between 2 and 20 fold and most preferably between 4 and 16 fold. While no particular restrictions are placed on the dilution technique, similar to the extraction process, it is recommended to use water.
Moreover, the solvent can be removed from the stock solution using various appropriate concentrating methods to prepare solid extracts.
For compositions prepared in such a manner, whether in a solution or suspension state, preferably the compositions have an oxidation-reduction potential of about +1230 mV or less. More preferably, the compositions have an oxidation-reduction potential of about +900 mV or lower. Such compositions have exhibited potent anti-tumor activity.
The oxidation-reduction potential value is measured in an aqueous solvent, and preferably in water. The oxidation-reduction potential can be measured directly in the above-described stock solution or in a water-diluted solution. If the composition has been solidified, the solid should be dissolved or suspended using an adequate solvent, such as water, before measuring the oxidation-reduction potential.
As used herein, the oxidation-reduction potential of a solution of a particular composition is determined as follows. The oxidation-reduction potential is the potential of an oxidation-reduction electrode observed when the electrode is dipped into a test solution. In case of using reference electrode, a single potential of the reference electrode, which is the potential difference between an oxidation-reduction electrode (e.g. platinum electrode) and reference electrode is first determined. Thereafter, the reference electrode of the electrode potential measuring device is placed in the test solution and the potential difference is noted. The potential difference noted for the test solution plus the single potential is the oxidation-reduction potential for the solution. For example, if a platinum test electrode and a reference electrode (for example, AgCl (internal solution 3.3 mol/l KCl)) are used, the potential obtained by adding the single-electrode potential of the reference electrode with the potential difference between the reference electrode and the test solution is the oxidation-reduction potential. Throughout this specification, the oxidation-reduction potential was measured at a test solution temperature of 25xc2x0 C.
After the composition is prepared or after it is dissolved or suspended, its oxidation-reduction potential typically changes over time. The oxidation-reduction potential should therefore be checked from time to time. Preferably, the solution is used when the oxidation-reduction potential is about +900 mV or less. The oxidation-reduction potential of the composition should also be checked before each administration. Preferably, the composition and solutions thereof are stored at 25xc2x0 C. and the temperature in the measurement room should also be 25xc2x0 C.
The oxidation-reduction potential of the resulting composition appears to be significant because, especially for compositions having an oxidation-reduction potential of +900 mV or less, a negative correlation exists between the oxidation-reduction potential of the composition and its anti-tumor activity. In other words, the lower the oxidation-reduction potential, the stronger the anti-tumor activity.
As a result, the anti-tumor activity and hypoglycemic effect of the subject composition can be estimated before administering the composition by measuring its oxidation-reduction potential before the composition is administered. In this manner, treatment efficacy can be increased.
In more particularly preferred compositions of the present teaching, the oxidation-reduction preferably is +330 mV or lower, more preferably is +300 mV or lower and most preferably is +250 mV or lower. Further, the oxidation-reduction preferably is xe2x88x921200 mV or higher and more preferably is xe2x88x92300 mV or higher.
The present compositions may comprise only Basidiomycotina extracted components and Araliaceae plant root extracted components. However, other active or inactive ingredients can also be included as long as the additional ingredients do not inhibit the synergistic effect of the above-mentioned 2 extracted components. For example, the extracted components described herein can be mixed with pharmaceutically acceptable carriers and additives in order to prepare compositions suitable for administration. While no special restrictions are placed on form, the compositions can be manufactured in the form of a solution, syrup, suspension, emulsion, granules, tablets, pills, capsules, cream, lozenge, chewable tablets, suppository, eye drops, injection, aerosol, elixir and the like. The present compositions also can be used in a solid (powder) form and solutions can be reconstituted by adding water at the time of administration. Thus, various administration routes are available for the present compositions.
The present compositions have been shown to have anti-tumor activity, especially with respect to leukemia, cervical carcinoma, lung carcinoma, cancer of the ovaries, breast cancer (including metastatic cancer) and cutaneous carcinoma (including metastatic cancer). An example of leukemia is erythroblastic leukosis. Thus, the present compositions can be used as anti-tumor agents for mammals, including for example humans, primates, cattle, horses, dogs and cats.
While the extracted components of Basidiomycotina are known to have anti-tumor activity and the extracted components of the root of Araliaceae plants are known to have an anti-tumor activity, the present compositions have demonstrated an unexpectedly potent anti-tumor activity, as compared to the anti-rumor activities of the individual components.
In addition, the present compositions also have a hypoglycemic effect and the present compositions have been shown to be effective in both insulin dependent diabetes mellitus and non-insulin dependent diabetes mellitus.
Moreover, the present compositions have not demonstrated any adverse effects. In fact, the present compositions may be useful to reduce and alleviate the adverse effects of other drugs.
For example, when the present compositions have been administered to human patients as anti-tumor agents, the compositions have demonstrated various beneficial effects, such as alleviating pain, improving appetite and enabling the patient to sleep well, in addition to causing tumors to heal or regress. When administered to humans to reduce blood sugar levels, the present composition again demonstrated various beneficial effects, such as alleviating pain in the body, especially significantly relieving headaches and numbness of the limbs, increasing appetite, recovering eyesight, reducing stress and enabling the patient to sleep well, in addition to causing blood glucose levels to decrease.
While the present compositions can be administered in therapeutically effective amounts either orally or parenterally, preferably the compositions are administered orally. General doses appropriate for oral administration are indicated below. Naturally, the dose should be appropriately adjusted according to the patient""s symptoms and stamina. Generally speaking, usual or normal dosages are, for example, a daily dosage of the extracted components obtained from between 200 mg and 2 g Basidiomycotina and between 100 mg and 1 g root of an Araliaceae plant, per 1 kg of body weight. These doses are preferably administered between 1 and 3 times per day.
Especially when used as an anti-tumor agent, preferably the extracted components are administered that have been extracted from raw materials in a ratio of about 0.27 g Basidiomycotina and the root of an Araliaceae plant per 1 kg of body weight per day. More preferably, the extracted components are administered that have been obtained from raw materials in a ratio of about 0.18 g Basidiomycotina/1 kg of body weight/day and the extracted components obtained from about 0.09 g, root of an Araliaceae plant/1 kg body weight/day.
When used as a hypoglycemic agent, preferably the extracted components are administered that have been extracted from raw materials in a ratio of about 0.12 g Basidiomycotina and the root of an Araliaceae plant/1 kg of body weight/day. More preferably, the extracted components are administered that have been obtained from raw materials in a ratio of about 0.08 g Basidiomycotina/1 kg body weight/day and the extracted components obtained from about 0.04 g root of an Araliaceae plant/1 kg body weight/day.
When used as a hypoglycemic agent (i.e. to reduce blood sugar levels), the composition is preferably administered together with water and/or alcohol extracts of the root of an Araliaceae plant. Such alcohol extracts can be obtained by using the root of an Araliaceae plant, preferably medicinal ginseng and most preferably Panax japonicus, in the form of splinters or powder (preferably splinter approximately 5 mm in size). Between about 300 and 600 parts per weight of a 40% ethyl alcohol solution is added to between 10 and 20 parts per weight of the splinters. Heat-extraction is performed by beating the solution to between 80 and 100xc2x0 C. until the alcohol evaporates almost completely.
Because the toxicity of the present compositions appears to be very low and does not appear to cause serious adverse effects, a high dose can also be safely administered if needed, based upon the symptoms.
The recommended dosage form for oral administration is solution or syrup. Water is recommended as the administration medium.
In summary, the following representative aspects of the present teachings are provided herein:
(1) Compositions comprising a therapeutically effective amount of active ingredients found in one or more types of Basidiomycotina that belong to polyporaceae Basidiomycotina and the root of a plant that belongs to Araliaceae. These active ingredients may be prepared synthetically or by isolation from natural products. In a preferred aspect of the present teachings, a ratio of between about 0.5 and 2 parts per weight of the root of an Araliaceae plant to 2 parts per weight Basidiomycotina is utilized and the active ingredients are isolated therefrom. Such compositions have shown hypoglycemic (blood sugar reducing) effects.
(2) The above-mentioned compositions of paragraph (1), wherein the above-mentioned one or more types of Basidiomycotina are Ganoderma Lucidum and/or Coriolus versicolor. 
(3) The above-mentioned compositions according to paragraphs (1) and (2), wherein the above-mentioned plant that belongs to Araliaceae is medicinal ginseng.
(4) The above-mentioned compositions according to paragraphs (1) through (3), wherein the above-mentioned Araliaceae plant is Panax ginseng and/or Panax japonicus. 
(5) The above-mentioned compositions according to paragraphs (1) through (4), wherein the oxidation-reduction potential is +1230 mV or less.
(6) Compositions comprising a therapeutically effective amount of hot-water extracted components of one or more types of Basidiomycotina that belong to polyporaceae Basidiomycotina and the hot water extracted components of the root of a plant that belongs to Araliaceae. Additional compositions include such extracted components in a solution containing 40% or more alcohol and the root of a plant that belongs to Araliaceae.
(7) The above-mentioned compositions according to paragraph (6) which have a hypoglycemic effect.
(8) Compositions comprising extracted components of one or more types of Basidiomycotina that belong to polyporaceae Basidiomycotina and extracted components of the root of a plant that belongs to Araliaceae.
(9) Method for treating patients by administering a therapeutically effective amount of a composition according to any of paragraphs (1) through (8). For example, such compositions may be administered to patients whose blood glucose level should be reduced.
(10) Compositions comprising active ingredients of one or more types of Basidiomycotina that belong to polyporaceae Basidiomycotina and the root of a plant that belongs to Araliaceae. These active ingredients may be prepared synthetically or by isolation from natural products. Preferably, a ratio of between 0.5 and 2 parts per weight of the root of an Araliaceae plant to 2 parts per weight Basidiomycotina is utilized and the active ingredients are isolated therefrom. Such compositions have shown anti-tumor activity.
(11) The above-mentioned compositions according to paragraph (10), wherein the above-mentioned one or more types of Basidiomycotina is Ganoderma Lucidum and/or Coriolus versicolor. 
(12) The above-mentioned compositions according to paragraphs (10) and (11), wherein the above-mentioned plant that belongs to Araliaceae is medicinal ginseng.
(13) The above-mentioned compositions according to paragraphs (10) through (12), wherein the above-mentioned plant that belongs to Araliaceae is Panax ginseng and/or Panax japonicus. 
(14) The above-mentioned compositions according to paragraphs (5) through (8) and (10) through (13), wherein the oxidation-reduction potential is +1230 mV or less.
(15) Methods for treating patients by administering a therapeutically effective amount of a composition according to any of paragraphs (10) through (14). Such compositions may, for example, be administered to patients having tumors and preferably to patients that have been diagnosed with terminal cancer.
(16) Compositions comprising components extracted from about 10 parts per weight Coriolus versicolor and between about 1.5 and 6 parts per weight Panax japonicus to about 5 parts per weight Ganoderma Lucidum. 
(17) The above-mentioned compositions according to paragraph (16), wherein the oxidation-reduction potential is +1230 mV or less.
(18) Methods for treating patients by administering a therapeutically effective amount of a composition according to any of paragraphs (16) and (17).
Other aspects of the present teachings are also provided throughout the specification.
Each of the additional examples, compositions and method steps disclosed above and below may be utilized separately or in conjunction with other examples to provide improved compositions and methods for making and using such compositions. Representative examples of the present invention, in which such examples, compositions and method steps are in conjunction or in farther detail, will now be described. This detailed description is merely intended to teach a person of skill in the art further details for practicing preferred aspects of the present teachings and is not intended to limit the scope of the invention. Only the claims define the scope of the claimed invention. Therefore, combinations of features and steps disclosed in the following detail description may not be necessary to practice the invention in the broadest sense, and are instead taught merely to particularly describe representative examples of the invention.